The COVID Vaccine: Why give two if one will do?

The COVID Vaccine: Why give two if one will do? 

The great COVID vaccine rollout of 2021 is fully underway. Armed with two highly effective products from Pfizer and  Moderna, with others soon to follow, our nation is rapidly advancing toward the  immunization of all Americans in hopes of stemming the  pandemic. We just can’t get there fast enough. Indeed, since the Pfizer vaccine was FDA approved,  250,000 more Americans have died from COVID.

And despite  tens of millions of vaccine doses having been administered, and millions more being given every week, countless Americans are  anxious about their risk, and  frustrated by their inability to get a timely appointment because our rollout understandably prioritizes  those at greatest risk. The others just have to wait. Or do they?

A clear drag on vaccine delivery is the requirement for  two doses per person. The obvious reason we are giving two doses is that this is how it was done in the clinical trials. In all fairness, the  pharmaceutical companies who planned these trials wanted to be sure their vaccines would clearly demonstrate a protective effect. And the  science suggested that the first dose would not be sufficient to achieve protection. It was to be a  primer for the second dose, which would get us all the way there and keep us there.  I have no argument with that decision. Before the clinical trial, we weren’t even sure that two doses would get us to where we needed to be. That’s why we conducted the trial.

But when the results were finally released, we were pleasantly surprised to learn that both the  Pfizer and  Moderna vaccines were extraordinarily effective. This was certainly an outcome to  celebrate. 

And when the  time period after the  first dose was compared to the time period after the  second, it did appear that the second dose was necessary. As you can see, the first dose was reported as  52% effective, and the second dose brought that up to  95%. It seemed that this comparison clinched the case for giving two shots. But that was not the full story. Let’s take a deeper dive into the evidence. 

The clinical trials that proved the Pfizer and Moderna vaccines are effective were fully reported in the  New England Journal of Medicine our pre-eminent scientific publication in my world of medicine. The  Pfizer study was published first, in December. This article reported that more than 40,000 subjects were randomly assigned by the equivalent of a  coin toss to receive either the  Pfizer vaccine or a  placebo injection, a dummy dose, on  day 0 and again on  day 21. The subjects were not told what they had received so that their personal behaviors could not affect the outcome of the study. Imagine if subjects in the vaccinated group started hanging out in  bars, believing it was now safe to do so. That could have really corrupted the results. So this study, appropriately, was blinded.

Now let’s take a look at those  results for ourselves.  They are best represented  here in figure 3, which shows COVID infections over the course of time. Each  blue square represents one or more infections in the  non-vaccinated, or placebo, group and each  red circle represents the same in the  vaccinated group. 

Moving from  left to right, we are advancing in the number of  days that have passed from the  first dose, given on day 0.  As  infections occur in each group, their curves climb upward.  Its easy to see that there is a huge difference in outcomes as the  vaccinated group curve totally flattens out while the  placebo group curve continues to climb upward at a steady pace. By the time these data were reviewed, the vaccine group had a huge advantage, experiencing  95% fewer infections than the placebo group. It is an astonishing result and a real tribute to the science behind the development of the vaccine. Three cheers for Pfizer and their German partner – BioNTech. 

But now that we are here, let’s take a closer look at the relationship between the vaccine response and the timing of the two doses, magnified in  this insert.  (pause).   We have always known that there is a natural delay for a first vaccine dose to take effect and this case was no exception. True to form, during the  first 10 days after the first Pfizer dose, there was virtually zero impact on COVID infections. See how these lines completely overlap?

But look what happens right around day  11. The two curves dramatically and completely split apart so that there are just a  few infections in the vaccine group over the next ten days, compared to  dozens in the placebo group. 

So why did the article report the first dose was only 52% effective? Well, it’s because they averaged the  first ten days, when the vaccine had no effect, with the  second ten-day period, when there was nearly full protection. When you average something near  0% with something close to  100%, you come out somewhere in the middle, which was  52%, the widely reported impact for the first dose. But that is mixing  apples and  oranges. Only when you analyze these  two 10-day periods  separately do you appreciate the nuance.

The  Moderna vaccine report , which was published in early February makes this even more clear. The  main difference here is that the second dose was given  28 days after the first. Let’s cut to the chase and go straight to  figure 3, which looks an awful lot like the Pfizer curve.  In this case it is a  94% decrease in COVID infections for the vaccinated group. What I love about this report is that they actually provided the numbers for each time period, in  this table below the graph.  

In the  first 14 days after dose #1, there were  11 infections in the control group and  5 infections in the vaccine group. That was a nice early positive trend. But in the  second 14-day period, there was an astounding difference:  35 vs.  2!  In other words, a  94% reduction in infections was evident in the two-week period before the second dose was given on day 28. We got there entirely with the first dose.

If we do not need the second dose in order to achieve a protective response, do we need it at all? Almost certainly we do. Because the effect of a first vaccine dose will typically fade over time, it is the booster dose that makes the protective effect durable. And that would be especially true for people who respond poorly to vaccines, such as the very old and infirm. This is what the science tells us. So we likely do need two. The question is how far apart. 

Which brings me to the  public health question. Should we be rolling out these vaccines as a  pair of doses several weeks apart, as we are doing, or should we wait to give the second dose until more people at  risk have received their first?  In a  perfect world, where we have an unlimited supply of vaccine, we should, of course, give the doses 3 or 4 weeks apart exactly as they were  studied in the clinical trials. That is an important principle of evidence-based medicine.

But in our  imperfect world where the  demand for vaccine initially has outstripped the  supply, giving someone their  second dose earlier means giving someone else their  first dose later. Delaying the first dose for any group will certainly result in  some deaths that could have been prevented by the vaccine. Whatever we decide, it is a  tradeoff we cannot escape.  

And this is why we have a  dilemma. We don’t actually know what is the impact of delaying the second dose. The  science does not take us all the way there. Let’s accept that. But we do know that delaying the first dose leaves folks without  any protection at all. To protect them earlier, we need to take a  leap of faith that the folks who already got their first dose will continue to be protected to an acceptable degree while waiting a bit longer for their second one.

In my world of medicine, I find it is often the case that the science does not take me all the way there, and I have to take my own leap of faith – incorporating nuances about a particular patient to get to my final decision. That process requires a strong scientific foundation, and also a willingness to be flexible when called for.

 So it is time for your test. You have  two patients in front of you and  two doses of vaccine to administer. You might think of them as your parents. The  next two doses will be arriving in six weeks. How are you going to dole these out? Will you give one patient their first dose  now, reserving the second dose for their  three week booster?  And leave the second patient unprotected until the sixth week, when they get  their first dose, followed by  their booster?   Or… will you give both their  first dose at once, hoping they will maintain immunity until week  six, when they both get their boosters?  Which approach do you think is most likely to save a life? Which plan seems most ethical?

Contrary to the  American approach, the  United Kingdom did make a controversial public policy decision to delay the second dose by twelve weeks so that more people could get their first dose earlier. Their  government has been criticized for departing from the recommended strategy of two doses 3 to 4 weeks apart. But by the time  34% of the UK population had received their first dose, only  19% of the US population had done so. As long as there is a limit to the vaccine supply, we will be facing this tradeoff.

This is a hard call. There are  two sides to this debate and fortunately everyone currently involved in these decisions:  scientists,  public health officials, and  national leaders, in both the US and the UK, have the best of intentions in making these gut wrenching decisions with pros and cons in either direction. But that  first dose is more effective than we could ever have hoped for, and I am suggesting that we should use this bounty of science to save as many lives as quickly as possible. 

Hi. I’m Nate Link, and I hope you were enlightened by this video essay on the timing of COVID vaccine doses.  For more essays on evidence-based politics, please visit my website at Snickersnack.com or read my book, The Ailing Nation, available on Amazon.